Epilepsy is a neurological disease that is characterized by paroxysmal transient disturbances of the electrical activity of the brain. Epileptic seizures may be partial or focal seizures that are restricted to a particular locus within the brain, or generalized seizures which can result in abnormal activity throughout the brain. The disturbances of brain function during an epileptic attack may be manifested as psychic or sensory incidents such as amnesia, hallucinations, deja vu states etc., as abnormal motor phenomenon such as spasms or whole body convulsions or as loss of consciousness. In extreme cases, epilepsy can degenerate into status epilepticus which may be fatal (DeLorenzo et al.--J. Clin. Neurophysiol. (1995) 12: 316-325).
Valproic acid (VPA) and its sodium salt (sodium valproate, NaVPA) are among the most prescribed anti-epileptic drugs. These drugs are also effective in the treatment of bipolar disorders and in prophylaxis of migraines.
Although the clinical usefulness of valproic acid is well established, this compound suffers major drawbacks. Treatment with VPA is associated with adverse side effects such as gastro-intestinal irritation, bone marrow suppression (especially manifested as aplastic anemia and thrombocytopenia), and hepatic dysfunction. VPA has also been reported to have teratogenic effects and patients treated with VPA may experience nausea, vomiting, dizziness, confusion or sedation.
Another drawback of valproic acid is its short half-life due to rapid clearance of the drug. As a result plasma levels of VPA fluctuate during chronic treatment and the drug has to be administered several times a day even as a sustained release formulation. In addition, valproic acid, which is a liquid, is less desirable for use as an oral dosage form. The sodium valproate, on the other hand, is solid, but being hygroscopic is characterized by poor stability.
Efforts have been made in order to overcome the VPA-induced side effects and the disadvantageous physical and pharmacokinetic properties of the drug. Most approaches that have been taken involve modification of the VPA molecule. However, although some of the modified drugs were devoid of adverse side effects, in many cases they also lost the therapeutic effect or were much less potent.
Mergen et al (J. Pharm. Pharmacol. (1991), 43: 815-816) describe conjugates of valproic acid with 1,3-dipalmitoylglycerol, 1,2-dipalmitoylglycerol or 1,3-diaminopalmitoyl-propan-2-ol. According to the Mergen et al.'s publication, only the latter compound was found to have antiepileptic activity, while both conjugates of VPA with the diglycerides were inactive.
Hadad et al. (Biopharmaceutics & Drug Disposition (1993), 14: 51-59) investigated the anticonvulsant activity of 1,4-butanediol divalproate, glyceryl trivalproate and valpromide in comparison to valproic acid. Their study demonstrated that only 1,4-butanediol divalproate, in one of the model systems tested, had a better protective index value than VPA.
U.S. Pat. No. 4,654,370 to Marriott and Paris discloses glycerides esterified with one or two moles of valproic acid. These compounds have been found to have the same useful therapeutic effect as valproic acid alone but without causing gastric irritation.
U.S. Pat. Nos. 4,988,731 and 5,212,326 both to Meade, disclose oligomers having 1:1 molar ratio of sodium valproate and valproic acid which have physiological properties similar to those of valproic acid or sodium valproate but show superior stability characteristics.
U.S. Pat. No. 4,558,070 to Bauer and Shada discloses a stable complex between valproic acid and potassium, cesium or rubidium which may be formed by combining four moles of valproic acid with one mole of the alkali metal ion. The alkali metal salts of valproic acid were reported to have improved stability.
Despite continuous efforts in the field, it is still an unmet need to provide an anti-epileptic medication with improved pharmacokinetic properties and overall superior therapeutic index.